Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties, including tumor necrosis factor α (TNF-α).
A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; arthritis; and proliferative vitreoretinopathy.
Certain 4′-arylmethoxy isoindoline compounds, including 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, have been reported to be capable of controlling angiogenesis or inhibiting the production of certain cytokines, including TNF-α, and useful in the treatment and prevention of various diseases and conditions. See U.S. Patent Publication No. 2011/0196150, which is incorporated herein by reference in its entirety.
Methods for synthesizing racemic 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione have been previously described in U.S. Patent Publication No. 2011/0196150. A need still exists for efficient and scalable processes for the preparation of enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable form thereof.
Among general approaches for providing enantiomerically enriched or enantiomerically pure compounds, utilizing naturally or commercially available enantiopure starting materials is the most straightforward approach and is often preferred for processes of industrial scale. One of the challenges often encountered by this approach is full or partial racemization during the synthetic process, which leads to decrease of the enantiomeric excess (ee) of the material. In order to minimize the chance of racemization, harsh reaction conditions are often avoided wherever possible.
In addition to the need for synthetic processes for the preparation of an enantiomerically enriched or enantiomerically pure compound, a need for a method that can increase the enantiopurity of a compound still exists, because process deviations can result in lower ee even if the process is capable of providing the compound with a high ee. Further, developing a method that can increase the product ee may allow for alternative synthetic routes to the enantiomerically enriched or enantiomerically pure compound, resulting in lower cost of goods and a more streamlined manufacturing process.
General methods for ee enhancement by crystallization based on the thermodynamic relationship between racemic mixture and enantiopure species have been reported (Wang et al., Org. Proc. Res. Dev., 2005, 9, 670; Wang et al., Org. Proc. Res. Dev., 2008, 12, 282; Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolution; John Wiley & Sons: New York, 1981). Development of a crystallization method for a direct ee enhancement typically includes three steps: (1) determining the thermodynamically stable phase of the racemate (conglomerate, racemic compound, or pseudoracemate) at the temperature of interest, (2) obtaining the key solubility data, and (3) designing the crystallization process.
The majority of racemic mixtures preferentially form racemic compounds (reference Jacques book). The saturation solubility of a racemic compound and the pure enantiomer in the presence of a solvent is known as the eutectic point. The ratio of the solubility, i.e., the “eutectic enantioexcess” (eeeu), is a useful parameter to assess the chiral upgrade capability for a given system. The eeeu is calculated from the relative solubility of the R- and S-enantiomers: eeeu=([major]−[minor])/([major]+[minor]), where [major] is the solubility of the major enantiomer at the eutectic, and [minor] is the solubility of the minor enantiomer at the eutectic. Provided that the most stable crystalline forms of the racemic compound and single enantiomer are used, in dilute solutions, the eeeu should be independent of solvent selection, unless one or both of the forms are solvates and/or the solvent under study is chiral. The eeeu can be dependent on temperature in all cases.
In the case of racemic compound, low eeeu is desired to increase ee of a compound in the solids. This occurs when the racemic compound has relatively high solubility compared to the single enantiomer. In the case of a low eeeu, facile purification can occur by a trituration or recrystallization of the crude mixture in a specified solvent, followed by filtration, which will afford enantiomerically enriched or enantiomerically pure solids with a mixture of both enantiomers dissolved in the filtrate.
Identifying a low eeeu condition often requires extensive solubility screening of a range of crystalline forms, solvents and conditions, and in many cases still cannot be achieved.